Student engagement in a Human Anatomy and Physiology course: a New Zealand perspective.

The population diversity of New Zealand is due to the unique fusion of indigenous peoples of Polynesian origin (Maori), western European colonization (Pakeha), and more recent (20th century) immigration from the Pacific region (Pasifika). However, disparities in tertiary education indicate that Maori and Pasifika students are more likely to drop out during their first year of study and are less likely to complete their qualification than their Pakeha peers. Higher levels of course engagement may increase first-year grades, elevate academic performance, and encourage persistence between the first and second years of study. Therefore, a Student Course Engagement Questionnaire was used to quantify engagement in a compulsory first-year undergraduate Human Anatomy and Physiology course in a New Zealand university. A data mining technique was used to assign students into a low-engagement/low-achievement cluster, and a high-engagement/high-achievement cluster. The skills, emotional, and participation-interaction components of engagement were lower in Pasifika students: these students' academic grade was lower than those of both Maori and Pakeha students. The strongest predictors of cluster membership were skills engagement and emotional engagement, suggesting that these components outweighed other aspects of course engagement. Maori and Pasifika students were overrepresented in the low-engagement/low-achievement cluster, and underrepresented in the high-engagement/high-achievement cluster. We suggest that embedding study skills within course delivery, and constantly emphasizing their importance, would likely increase student course engagement. Also, we report that both Maori and Pasifika students remain more disengaged than their Pakeha peers.

Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study.

BACKGROUND: HIV-associated diarrhea remains a significant concern with limited treatment options. OBJECTIVE: To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea. METHODS: This randomized, double-blind, phase 3 trial used a 2-stage design. Both stages included 2-week screening, 4-week placebo-controlled treatment, and 20-week placebo-free (open-label) extension phases. In stage I, 196 HIV-seropositive patients with chronic diarrhea were randomized to crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. Using a prospective analysis, the 125-mg twice-daily dose was selected for stage II. In stage II, 180 new patients were randomized to crofelemer 125 mg twice daily or placebo for 4 weeks. Primary efficacy analysis was the percentage of patients (stages I/II combined) who achieved clinical response (defined as ≤2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (≤2 watery stools) was assessed weekly. RESULTS: Significantly more patients receiving crofelemer 125 mg achieved clinical response versus placebo (17.6% vs 8.0%; one-sided, P = .01). Crofelemer 125 mg resulted in a greater change from baseline in number of daily watery bowel movements (P = .04) and daily stool consistency score (P = .02) versus placebo. During the placebo-free extension phase, percentages of weekly responders ranged from 40% to 56% at weeks 11 to 24. Crofelemer was minimally absorbed, well tolerated, did not negatively impact clinical immune parameters, and had a safety profile comparable to placebo. CONCLUSIONS: In HIV-seropositive patients taking stable antiretroviral therapy, crofelemer provided significant improvement in diarrhea with a favorable safety profile.

Human cardiac autonomic responses to head-up tilting during 72-h starvation.

Starvation may change autonomic nervous system activity and sensitivity such that a greater vagal withdrawal may occur during a sympathetic challenge. Six healthy humans endured a 3-day, water-only fast, during which participants were subjected to passive 80° head-up tilt testing twice on each day (a.m. and p.m.). Heart rate, heart rate variability (HRV), ventilation [Formula: see text], and respiration ([Formula: see text] and [Formula: see text]) were recorded during supine rest and head-up tilting. On Day 1 (a.m.), supine heart rate was 46.0 ± 3.3 beats min(-1), increasing to 51.6 ± 7.4 beats min(-1) on Day 3 (p.m.). On Day 1 (a.m.), supine high frequency HRV was 57.9 ± 31.6(NU), increasing to 69.5 ± 21.3(NU) on Day 3 (p.m.). Tilt-induced increases in heart rate were greater following starvation (10.5 ± 7.8 vs. 16.1 ± 8.6 beats min(-1)), and tilt-induced decreases in high frequency HRV were greater following starvation (-4.1 ± 27.7 vs. -28.0 ± 20.8(NU)). Supine V'CO(2) remained unchanged, whereas V'O(2) increased and respiratory exchange ratio decreased (0.91 ± 0.10 vs. 0.80 ± 0.05). Greater vagal withdrawal and elevated heart rate induced by head-up tilting during starvation may indicate increased autonomic sensitivity.

Interactions between heart rate variability and pulmonary gas exchange efficiency in humans.

The respiratory component of heart rate variability (respiratory sinus arrhythmia, RSA) has been associated with improved pulmonary gas exchange efficiency in humans via the apparent clustering and scattering of heart beats in time with the inspiratory and expiratory phases of alveolar ventilation, respectively. However, since human RSA causes only marginal redistribution of heart beats to inspiration, we tested the hypothesis that any association between RSA amplitude and pulmonary gas exchange efficiency may be indirect. In 11 patients with fixed-rate cardiac pacemakers and 10 healthy control subjects, we recorded R-R intervals, respiratory flow, end-tidal gas tension and the ventilatory equivalents for carbon dioxide and oxygen during 'fast' (0.25 Hz) and 'slow' paced breathing (0.10 Hz). Mean heart rate, mean arterial blood pressure, mean arterial pressure fluctuations, tidal volume, end-tidal CO(2), and were similar between pacemaker and control groups in both the fast and slow breathing conditions. Although pacemaker patients had no RSA and slow breathing was associated with a 2.5-fold RSA amplitude increase in control subjects (39 +/- 21 versus 97 +/- 45 ms, P < 0.001), comparable (main effect for breathing frequency, F(1,19) = 76.54, P < 0.001) and reductions (main effect for breathing frequency, F(1,19) = 23.90, P < 0.001) were observed for both cohorts during slow breathing. In addition, the degree of (r = 0.36, P = 0.32) and reductions (r = 0.29, P = 0.43) from fast to slow breathing were not correlated to the degree of associated RSA amplitude enhancements in control subjects. These findings suggest that the association between RSA amplitude and pulmonary gas exchange efficiency during variable-frequency paced breathing observed in prior human work is not contingent on RSA being present. Therefore, whether RSA serves an intrinsic physiological function in optimizing pulmonary gas exchange efficiency in humans requires further experimental validation.

Effects of eccentric exercise-induced muscle damage on intramyocellular lipid concentration and high energy phosphates.

Eccentric exercise is known to cause changes to the ultrastructure of skeletal muscle and, in turn, may alter the ability of the muscle to store and utilise intracellular substrates such as intramyocellular lipid (IMCL). The purpose of this study was to test the hypothesis that exercise-induced muscle damage (EIMD) results in IMCL accumulation. Six males (31 ± 6 years; mean ± SD, and 72.3 ± 9.7 kg body mass) performed 300 unilateral, maximal, isokinetic, eccentric contractions (Ecc) (30° s(-1)) of the quadriceps on an isokinetic dynamometer, followed immediately by an equal amount of work by the contralateral leg but with concentric action (Con). Phosphate compounds and IMCL content of the vastus lateralis of both legs were measured using (31)P and (1)H magnetic resonance spectroscopy. IMCL content was higher in Ecc than Con 24 h post but the reverse was evident 48 h post-exercise (P = 0.046). A significant time × trial interaction for resting [P(i)] (P = 0.045), showed increases in Ecc across time but no change in Con. A significant main effect of trial (P = 0.002) was apparent indicating the Ecc leg had marked metabolic dysfunction. The P(i)/PCr ratio showed a significant effect of trial (P = 0.001) with an increase evident in Ecc leg, primarily due to increases in [P(i)]. The present study highlights changes in IMCL content of skeletal muscle following EIMD.

Safety and immunogenicity of a replication-incompetent adenovirus type 5 HIV-1 clade B gag/pol/nef vaccine in healthy adults.

BACKGROUND: The safety and immunogenicity of the MRK adenovirus type 5 human immunodeficiency virus type 1 clade B gag/pol/nef vaccine, a replication-incompetent adenovirus type 5-vectored vaccine designed to elicit cell-mediated immunity against conserved human immunodeficiency virus proteins, was assessed in a phase 1 trial. METHODS: Healthy adults not infected with human immunodeficiency virus were enrolled in a multicenter, dose-escalating, blind, placebo-controlled study to evaluate a 3-dose homologous prime-boost regimen of the trivalent MRK adenovirus type 5 human immunodeficiency virus type 1 vaccine containing from 3 x 10(6) to 1 x 10(11) viral particles per 1-mL dose administered on day 1, during week 4 and during week 26. Adverse events were recorded for 29 days after each intradeltoid injection. The primary immunogenicity end point was the proportion of study participants with a positive unfractionated Gag-, Pol-, or Nef-specific interferon-gamma enzyme-linked immunosorbent spot response measured 4 weeks after administration of the last dose. RESULTS: Of 259 randomized individuals, 257 (99%) received > or = 1 dose of vaccine or placebo and were included in the safety analyses. Enzyme-linked immunosorbent spot results were available for 217 study participants (84%) at week 30. No serious vaccine-related adverse events occurred. No study participant discontinued participation because of vaccine-related adverse events. The frequency of injection-site reactions was dose dependent. Vaccine doses of > or = 3 x 10(9) viral particles elicited positive enzyme-linked immunosorbent spot responses to > or = 1 vaccine component in > 60% of recipients. High baseline antibody titers against adenovirus type 5 diminished enzyme-linked immunosorbent spot responses at all doses except the 3 x 10(10) viral particle dose. CONCLUSIONS: The vaccine was generally well tolerated and induced cell-mediated immune responses against human immunodeficiency virus type 1 peptides in most healthy adults. Despite these findings, vaccination in a proof-of-concept trial with use of this vaccine was discontinued because of lack of efficacy.

An open-label pilot study of high-concentration capsaicin patch in painful HIV neuropathy.

Peripheral neuropathy is the most frequent neurological complication of human immunodeficiency virus (HIV)-1 infection and is commonly associated with the development of chronic pain. This open-label, 12-week pilot study assessed the efficacy, tolerability, and safety of a high-concentration capsaicin dermal patch (NGX-4010; capsaicin, 640microg/cm2, 8% w/w) to treat painful HIV-associated distal sensory polyneuropathy (DSP). Eligible patients had moderate-to-severe pain in both feet due to HIV-associated DSP or antiretroviral toxic neuropathy. Patients received a single 60-minute application of the investigational high-concentration capsaicin patch to the affected areas. The primary outcome measure was the mean percent change in numeric pain rating scale (NPRS) during weeks two to 12 postadministration. After a single 60-minute NGX-4010 application, the mean percent change from baseline in "average pain for past 24 hours" NPRS scores during weeks two to 12 was -40% (95% CI: -61%, -19%; P=0.0020). Similar results were observed for "worst pain for past 24 hours" and "pain now" scores. Eight of 12 patients (67%) were treatment responders (> or =30% pain decrease). Four of 12 patients (33%) experienced a > or =50% reduction in pain. Treatment was generally well tolerated. Treatment-associated pain was self-limited and could be managed with short-acting opioids. This study demonstrates that treatment of painful HIV-associated neuropathy with a single application of NGX-4010, a high-concentration capsaicin patch, was feasible, well tolerated, and associated with significant reduction in pain over the 12 weeks studied. No safety concerns were identified. Controlled studies of NGX-4010 for the treatment of painful HIV-associated neuropathy are warranted.

Two-year prospective study of major depressive disorder in HIV-infected men.

OBJECTIVE: The risks and factors contributing to major depressive episodes in HIV infection remain unclear. This 2-year prospective study compared cumulative rates and predictors of a major depressive episode in HIV-infected (HIV+) men (N=297) and uninfected (HIV-) risk-group controls (N=90). METHODS: By design participants at entry were without current major depression, substance dependence or major anxiety disorder. Standardized neuromedical, neuropsychological, neuroimaging, life events, and psychiatric assessments (Structured Clinical Interview for DSM III-R) were conducted semi-annually for those with AIDS, and annually for all others. RESULTS: Lifetime prevalence of major depression or other psychiatric disorder did not differ at baseline between HIV+ men and controls. On a two-year follow-up those with symptomatic HIV disease were significantly more likely to experience a major depressive episode than were asymptomatic HIV+ individuals and HIV-controls (p<0.05). Episodes were as likely to be first onset as recurrent depression. After baseline disease stage and medical variables associated with HIV infection were controlled, a lifetime history of major depression, or of lifetime psychiatric comorbidity (two or more psychiatric disorders), predicted subsequent major depressive episode (p<0.05). Neither HIV disease progression during follow-up, nor the baseline presence of neurocognitive impairment, clinical brain imaging abnormality, or marked life adversity predicted a later major depressive episode. LIMITATIONS: Research cohort of men examined before era of widespread use of advanced anti-HIV therapies. CONCLUSIONS: Symptomatic HIV disease, but not HIV infection itself, increases intermediate-term risk of major depression. Prior psychiatric history most strongly predicted future vulnerability.

Age-Associated Changes In VO2 and Power Output - A Cross-Sectional Study of Endurance Trained New Zealand Cyclists.

Age-associated changes in power and maximal oxygen consumption (VO2max) were studied in a cross section of endurance trained cyclists. Subjects (n = 56) performed incremental cycling exercise, during which capillary blood lactate [La(-)] was measured. Power output increased by 30 Watts during each 5 minutes stage, with initial power output based on individual ability. When [La(-)] was >4.5 mmol·L(-1), subjects were given a 10 min recovery at a power output approximately 50% below estimated power at [La(-)]4mmol. Subjects then performed an incremental test (1 minute stages) to VO2max. Decline in VO2max was 0.65 ml·kg(-1)·min(-1)·year(-1) (r = -0.72, p < 0.01) for males, and 0.39 ml·kg(-1)·min(-1)·year(-1) (r = -0.54, p < 0.05) for females. Power at VO2max decreased by 0.048 W kg(-1)·year(-1) (r = -0.72, p < 0.01) in males. Power at [La(-)]4mmol decreased by 0.044 W kg(-1)·year(-1) (r = -0.76, p < 0.01) in males, and by 0.019 W kg(-1)·year(-1) (r = -0.53, p < 0.05) in females. Heart rate at VO2max (HRmax) showed a weaker correlation with age in males (r = -0.36, p < 0.05). The age-associated changes in maximum aerobic power and sub-maximal power were gender- specific, thus suggesting different age-related effects on the systems which support exercise in males and females. Key pointsVO2max decreased with age by 0.65 ml·kg(-1)·min(-1)·year(-1) in male, and by 0.39 ml·kg(-1)·min(-1)·year(-1) in female endurance trained cyclists.Power at VO2max decreased with age by 0.048 Watts·kg(-1)·year(-1) in male endurance trained cyclists.Sub-maximal power at a blood lactate concentration of 4mmol·L(-1) decreased by 0.044 Watts·kg(-1)·year(-1) in male, and by 0.019 Watts·kg(-1)·year(-1) in female endurance trained cyclists.

Prostratin induces HIV activation and downregulates HIV receptors in peripheral blood lymphocytes.

Induction of HIV expression through lymphocyte activation has been proposed as a strategy to purge latent reservoirs. Prostratin is a non-tumourogenic phorbol ester that delays HIV replication in vitro, but paradoxically activates HIV expression in latently infected cells. To get a better insight into the mechanisms of action of prostratin, we have analysed the effect of prostratin on HIV activation and HIV receptor and coreceptors' surface expression in human lymphocytes. Peripheral blood mononuclear cells (PBMCs) were transfected with luciferase expression constructs under the control of wild type HIV-long terminal repeat (LTR) and consensus sequences for transcription factors involved in HIV-LTR transactivation (NF-kappaB, SP1, NFAT). Prostratin stimulates transactivation of LTR vectors, kappaB- and SP-1-driven luciferase constructs. In another set of experiments, PBMCs were transfected with a full-length infectious viral clone. Prostratin induced HIV transcription and viral expression as detected by luciferase activity in cellular extracts and p24 levels in culture supernatants, respectively. Expression of the HIV coreceptors CCR5 and CXCR4 was decreased by prostratin and, concomitantly, prostratin inhibited the infection of PBMCs with R5 and X4 strains. However, prostratin did not inhibit infection with a pseudotyped viral clone that enters into the cells independently of HIV receptors. These results help to explain the paradoxical effects of prostratin. On one hand, prostratin induces HIV activation in latently infected cells through the induction of NF-kappaB and Sp1. On the other hand, strong and persistent downregulation of HIV receptors decreases infection of new targets and delays HIV propagation. These data support the potential use of prostratin to activate HIV from latency and purge viral reservoirs.

Mechanisms of HIV receptor and co-receptor down-regulation by prostratin: role of conventional and novel PKC isoforms.

Prostratin is an unusual non-tumour promoting phorbol ester with potential as an inductive adjuvant therapy for highly active antiretroviral therapy (HAART) due to its ability to up-regulate viral expression from latent provirus. In addition, prostratin is also able to inhibit de novo HIV infection most probably because it induces down-regulation of HIV receptors from the surface of target cells. In this study, we investigate the mechanisms by which prostratin down-regulates HIV receptor and co-receptor surface expression in lymphocytic and monocytic cell lines. Our results indicate that prostratin induces down-regulation of surface expression of CD4 and CXCR4, but not CCR5, in various cell lines. Down-regulation of CD4 and CXCR4 by prostratin is achieved by internalization through receptor-mediated endocytosis and/or macropinocytosis, which is then followed by degradation of these molecules. Because prostratin is a protein kinase C (PKC) activator, we next examined the potential contribution of distinct PKC isoforms to down-regulate CD4 and CXCR4 in response to prostratin stimulation. Although exposure of cells to prostratin or phorbol-myristate-acetate (PMA) induces the translocation of several PKC isoforms to the plasma membrane, the use of specific PKC inhibitors revealed that novel PKCs are the main mediators of the prostratin-induced CD4 down-regulation, whereas both conventional and novel PKCs contribute to CXCR4 down-regulation. Altogether these results showed that prostratin, through the activation of conventional and/or novel PKC isoforms, rapidly reduces cell surface expression of CD4 and CXCR4, but not CCR5, by inducing their internalization and degradation.

Potent and selective inhibition of HIV and SIV by prostratin interacting with viral entry.

Prostratin, a non-tumour promoting phorbol ester, exhibit a potent anti-HIV activity against human immunodeficiency virus type 1 (HIV-1). However, the antiviral mechanism of prostratin is not well defined. In the present study, we report that prostratin exhibits potent antiviral activity against different strains of HIV-1 (subtypes B and D), a clinical HIV isolate (L1), HIV-2 (ROD and EHO) and SIV (MAC251) with EC50-values ranging from 0.02-0.09 microg/ml. Prostratin was equally active against HIV strains resistant to the polyanionic binding inhibitor dextran sulphate, the fusion inhibitor T-20 (enfuvirtide), nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors (PIs). In contrast, prostratin lost 4.4- and 6.8-fold of its effect against the HIV strains resistant to AMD3100 and the quaternary ammonium salt QAS10+, respectively. As shown by time-of-addition experiments, prostratin needs to be present at the time of viral adsorption to exert its antiviral activity. We selected an HIV strain (NL4.3/PROS) resistant to prostratin in MT-4 cells. The sensitivity of NL4.3/PROS towards prostratin, dextran sulphate and QAS10+ was reduced by 3.2, 4.1 and >50-fold, respectively. However, NL4.3/ PROS was still sensitive to AMD3100, T-20, NRTIs (zidovudine and nevirapine) and a PI (ritonavir). Recombination of the gp160-gene of the NL4.3/PROS strain in a NL4.3 wild-type molecular clone fully rescued its phenotypic resistance. DNA sequencing of the NL4.3/PROS strain revealed mutations throughout the gp120 gene previously associated with resistance towards other HIV entry inhibitors. We concluded that prostratin inhibits the entry step of the replication cycle of HIV by interacting with a cellular target necessary for viral entry.

Effects of hypoxia and hypercapnia on human HRV and respiratory sinus arrhythmia.

PURPOSE: Hypercapnia increases minute ventilation (V'E) with little effect on heart rate (HR), whereas hypoxia may increase HR without affecting V'E. However, the effects of hypercapnia and hypoxia on both heart rate variability(HRV) and the clustering of heart beats during spontaneous breathing (respiratory sinus arrhythmia ­ RSA), are not clear. METHODS: In this study, 10 human volunteers breathed room air (RA), hypercapnic (5% CO2) or hypoxic (10%O2) gas mixtures, each for 6 min, while resting supine. ECG, mean arterial pressure (MAP), ventilatory flow, inhaled and exhaled fractions of CO2 and O2, were recorded throughout. RESULTS: Both V'E and MAP increased with 5%CO2, with no change in HR. Hypoxia did not change ventilation but increased HR. High frequency components of HRV, and the relative proportion of heart beats occurring during inhalation increased with 5% CO2, but neither changed with 10% O2. CONCLUSION: Increased RSA concomitant with increased MAP suggests RSA ­ vagal dissociation with hypercapnia. Elevated heart rate with acute hypoxia with no change in either frequency components of HRV or the distribution of heart beats during ventilation, suggested that clustering of heart beats may not be a mechanism to improve ventilation-perfusion matching during hypoxia.

Daily kiwifruit consumption did not improve blood pressure and markers of cardiovascular function in men with hypercholesterolemia.

Increasing fruit and vegetable consumption is a key lifestyle modification in the prevention and treatment of hypertension. Kiwifruit has previously been shown to have favorable effects on blood pressure (BP), likely through inhibiting angiotensin I-converting enzyme activity. We hypothesized that the replacement of 2 fruit servings in a healthy diet with 2 green kiwifruit a day would significantly improve BP and other markers of cardiovascular function, including heart rate, stroke volume, cardiac output, and total peripheral resistance, in a group of hypercholesterolemic men. Using a controlled cross-over study design, 85 subjects completed a 4-week healthy diet run-in period before randomization to one of two 4-week intervention sequences in which they either consumed 2 green kiwifruit a day plus a healthy diet (intervention) or consumed a healthy diet alone (control). Blood pressure and other measures of cardiovascular function (using a Finometer MIDI [Finapres Medical Systems B.V, Amsterdam, The Netherlands] and standard oscillometric device) and anthropometric measurements were taken before and at the end of the treatment periods. A physical activity questionnaire was completed during the last visit. Subjects were found to be predominantly normotensive (43.5%) or prehypertensive (50.6%) and quite physically active (>30 minutes of moderate to vigorous physical activity/day in >80% subjects). No significant differences were seen for BP or any of the other markers, including heart rate, stroke volume, cardiac output, and total peripheral resistance. In conclusion, in this hypercholesterolemic, nonhypertensive group, no beneficial effects on BP or other markers of cardiovascular function were seen when consuming 2 kiwifruit a day against the background of a healthy diet.

Ventilatory efficiency in juvenile elite cyclists.

OBJECTIVES: Ventilation ( [Formula: see text] ) as a function of CO2 output, and oxygen uptake ( [Formula: see text] ) as a function of [Formula: see text] , define cardio-respiratory efficiency, although few data compare efficiency with maximum oxygen uptake ( [Formula: see text] ), or consider reproducibility. Currently there are no data for trained juveniles. DESIGN: Twenty-five trained juvenile cyclists (mean age 14.7 years), performed maximal exercise testing on two occasions, separated by 16 weeks. METHODS: [Formula: see text] vs. [Formula: see text] slope, oxygen uptake efficiency slope, and [Formula: see text] were measured during cycle ergometer exercise to volitional exhaustion on two occasions, 16 weeks apart. RESULTS: Mean (SD) [Formula: see text] vs. [Formula: see text] slope, oxygen uptake efficiency slope, and [Formula: see text] were 28.14 (3.89), 4.16 (0.73), and 75.4 (8.9) mlkg(-1)min(-1) on visit 1, and 27.92 (4.63), 4.22 (0.76), and 73.6 (9.3) mlkg(-1)min(-1) on visit 2. Good reproducibility (differences ≤2.4%), but poor correlations (r≤0.29) between efficiency and [Formula: see text] were recorded. CONCLUSIONS: Reproducibility of efficiency measures was comparable to [Formula: see text] , however, poor associations between efficiency and [Formula: see text] suggested independence. Efficient ventilation may be of limited importance in determining the [Formula: see text] in a trained juvenile cyclist.

Sexual risk behaviors, circumcision status, and preexisting immunity to adenovirus type 5 among men who have sex with men participating in a randomized HIV-1 vaccine efficacy trial: step study.

BACKGROUND: The Step Study found that men who had sex with men (MSM) who received an adenovirus type 5 (Ad5) vector-based vaccine and were uncircumcised or had prior Ad5 immunity, had a higher HIV incidence than MSM who received placebo. We investigated whether differences in HIV exposure, measured by reported sexual risk behaviors, may explain the increased risk. METHODS: Among 1764 MSM in the trial, 726 were uncircumcised, 994 had prior Ad5 immunity, and 563 were both uncircumcised and had prior Ad5 immunity. Analyses compared sexual risk behaviors and perceived treatment assignment among vaccine and placebo recipients, determined risk factors for HIV acquisition, and examined the role of insertive anal intercourse in HIV risk among uncircumcised men. RESULTS: Few sexual risk behaviors were significantly higher in vaccine versus placebo recipients at baseline or during follow-up. Among uncircumcised men, vaccine recipients at baseline were more likely to report unprotected insertive anal intercourse with HIV-negative partners (24.9% vs. 18.1%; P = 0.03). Among uncircumcised men who had prior Ad5 immunity, vaccine recipients were more likely to report unprotected insertive anal intercourse with partners of unknown HIV status (46.0% vs. 37.8%; P = 0.05). Vaccine recipients remained at higher risk of HIV infection compared with placebo recipients (hazard ratio = 2.8; 95% confidence interval, 1.2-6.8) controlling for potential confounders. CONCLUSIONS: These analyses do not support a behavioral explanation for the increased HIV infection rates observed among uncircumcised men in the Step Study. Identifying biologic mechanisms to explain the increased risk is a priority .

Changes in human skeletal muscle length during stimulated eccentric muscle actions.

Following eccentric exercise, increases in muscle length alter the length-tension relation of skeletal muscle. However, its unclear if this change occurs during eccentric exercise. Therefore, 70 eccentric actions of the knee extensors of one leg (with superimposed electrical stimulation) were performed at 100°/s, from full extension to full flexion. Angle-specific eccentric force was recorded throughout. Force decreased at all angles although this was non-uniform. At 70°, force decreased by 25%, whereas at 130°, force decreased by 41%. Initial peak force was recorded at 100° (590 ± 232 N); the exercise bout induced a 21% decrease in peak force and a 10° shift in the position of peak force production to 90°. The rightward shift in the muscle length-tension relation thus occurred during eccentric exercise, where greater force loss at short muscle lengths suggested an eccentric-induced over-stretching of sarcomeres.

Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients.

BACKGROUND: HGS004 is a fully human immunoglobulin (Ig) G4 monoclonal antibody against CC chemokine receptor 5 (CCR5) with robust in vitro activity against a diverse panel of CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates. METHODS: A single-blind, randomized, placebo-controlled study was conducted in patients infected with CCR5-tropic HIV-1 to evaluate the safety, pharmacokinetics, and antiviral activity of HGS004. Sixty-three subjects were randomized into 5 dose cohorts (0.4, 2, 8, 20, and 40 mg/kg) and received a single intravenous dose of HGS004 or placebo. RESULTS: HGS004 was well tolerated, and no dose-limiting toxicities were observed. Pharmacokinetics were nonlinear across the 0.4-40-mg/kg dose range, with dose-proportional increases in maximum concentration, although the area under the curve increased more than proportionally to dose. High levels of receptor occupancy were observed for up to 28 days in the higher-dose cohorts. Plasma HIV-1 RNA reductions of >1 log(10) at day 14 were observed in 14 (54%) of 26 subjects in the 8-, 20-, and 40-mg/kg cohorts. In the 40-mg/kg cohort, 4 of 10 subjects had a >1 log(10) HIV-1 RNA reduction at day 28. Drug concentrations relative to isolate sensitivity (the ratio of the concentration at day 14 to IC(90)) predicted antiviral response on day 14. CONCLUSIONS: HGS004 is safe and well tolerated and demonstrates meaningful antiviral activity when administered to patients infected with CCR5-tropic HIV-1.

Recombinant human growth hormone to treat HIV-associated adipose redistribution syndrome: 12 week induction and 24-week maintenance therapy.

BACKGROUND: HIV-associated adipose redistribution syndrome (HARS) is an HIV-associated disorder characterized by excess truncal fat, including visceral adipose tissue (VAT). METHODS: From baseline to week 12 in this randomized, double-blind, placebo (PL)-controlled, multicenter trial investigating effects of recombinant human growth hormone (r-hGH; Serostim; EMD Serono Inc., Rockland, MA) in patients with HARS, 325 received induction (4 mg/d of r-hGH) or PL. At week 12, patients who initially received induction were rerandomized to 2 mg of r-hGH on alternate days (maintenance) or PL to week 36. Patients who initially received PL later received 4 mg/d of r-hGH. Change in VAT was the primary outcome. Key secondary outcomes included changes in non-high-density lipoprotein cholesterol (non-HDL-C) and limb fat. RESULTS: At week 12, induction therapy resulted in decreased VAT (-32.6 vs. 0.5 cm2; P<0.001), limb fat (-0.4 vs. 0.2 kg; P<0.001), and non-HDL-C (-13.0 vs. -2.8 mg/dL; P=0.023) compared with PL. On r-hGH induction-maintenance (baseline to week 36), patients sustained losses in VAT and trunk fat but not losses of subcutaneous fat in the abdomen or limbs. Also, non-HDL-C remained significantly decreased on r-hGH but not on PL maintenance. CONCLUSIONS: In patients with HARS, r-hGH induction-maintenance therapy produces greater relative losses of VAT and trunk fat than of subcutaneous fat and also has beneficial effects on the lipid profile.

The effects of breathing 5% CO2 on human cardiovascular responses and tolerance to orthostatic stress.

Breathing carbon dioxide (CO2) is known to induce hypercapnic acidosis and to affect chemoreceptor regulation of the cardiovascular system. However, there is limited information in the literature regarding the effects of breathing CO2 upon tolerance to orthostatic stress where cardiovascular regulation is challenged. The purpose of this study was to investigate the effect of breathing 5% CO2 on presyncopal tolerance to lower body negative pressure (LBNP). Nine subjects (five males and four females; average +/-s.d. age 21.9 +/- 0.9 years, height 172.4 +/- 9.7 cm, mass 70.3 +/- 7.1 kg) volunteered to participate in this study. Orthostatic tolerance was determined by exposing subjects to LBNP until the onset of presyncopal signs and symptoms on two occasions each separated by approximately 1 week. On one occasion investigations were carried out while subjects were breathing room air and on the other while subjects were breathing air containing 5% CO2, inducing hypercapnia and stimulating systemic chemoreceptors. During hypercapnic conditions, as compared with normocapnia, there were significant increases (P < 0.05) in minute ventilation, end-tidal CO2 and estimated arterial P(CO2). Furthermore, under hypercapnic conditions there was an increase in orthostatic tolerance, peak heart rate and time to peak heart rate during LBNP. The LBNP-induced increase in calf circumference was significantly attenuated at -50 mmHg of LBNP in addition to a further 22.3% reduction in stroke volume under hypercapnic conditions. In conclusion, these results suggest that the possible protective element of presyncope was delayed during hypercapnia at the expense of further reductions in stroke volume. This delayed presyncopal response may have been associated with increases in cerebral blood flow (CBF) induced by the increased arterial P(CO2).